Arthritis related diseases are the representative degenerative intractable diseases, which give 12% of total earth population pain. And over 2 million peoples are suffering from such diseases in Korea.
Arthritis is the general term for symptoms over all the musculoskeletal system caused by inflammatory changes in musculoskeletal and connective tissues. The disease is characterized by chronic inflammation causing permanent damage in tissues, deformity, degeneration and other troubles in joint, bone, cartilage and the spinal cord [Hofbause, L. C., Heufelder, A. E.: The role of osteoprotegerin and receptor activator of nuclear factor kappaB ligand in the pathogenesis and treatment of rheumatoid arthritis, Arthritis and Rheumatism 44:253-259, 2001]. Arthritis is classified into degenerative arthritis (osteoarthritis), rheumatoid arthritis, non-joint rheumatism and collagen disease.
Degenerative arthritis, which is the most common of all arthritis related diseases, is developed by local degeneration by the worn-out of joint cartilage. The cause of the disease is still unclear but aging or over-weight might be the reason. Primarily, degenerative changes appear in joint cartilage. Degeneration first begins in joint cartilage and chondrocytes are killed and then cartilage matrix is destroyed by cathepsin B, cathepsin D, collagenase, etc. The destruction outpaces the generation of proteoglycan and collagen, and adaptability of cartilage to outside force becomes weaker, resulting in microfractures in subchondral bone tissues. As the disease progresses, the hardening of subchondral bone, over-ossification around joint, joint deformation, etc. are observed. Then, the surface of cartilage becomes rough and inflammation in joint cavity enveloped by joint capsule repeats, resulting in constant pain, ankylosis and gradual motor disturbance in joint.
One kind of arthritis, rheumatoid arthritis is a chronic inflammatory disease over the whole body and its symptoms occur symmetrically to movable joints. The disease is also known as an autoimmune disease caused by malfunction of immune system. However, the cause of the disease is still in question. Rheumatoid arthritis is characterized by continuous inflammatory synovitis causing the destruction of cartilage and bone erosion, resulting in deformity of joint structure. Symptoms of rheumatoid arthritis are joint edema, joint tenderness, inflammation. Symptoms of osteoarthritis are morning stiffness and acute pain with bending of a joint. As the disease progresses, structural damage can be found such as bone erosion and joint destruction [Firestein, G. S.: Evolving concept of rheumatoid arthritis, Nature 423:356-361, 2003]. In addition, a patient with rheumatoid arthritis might suffer from other symptoms by additional organ damage, for example damage of skin, kidney, heart, lung, central nervous system and eye, which is resulted from vasculitis related to autoimmune process. Arthritis related other symptoms include acceleration of erythrocyte sedimentation rate and increase of the concentration of serum C-reactive protein (CRP) or soluble IL-2 receptor (IL-2r). The acceleration of erythrocyte sedimentation rate is detected in almost every active rheumatoid arthritis patients. The concentration of serum C-reactive protein also increases in those patients. It is related to the activation of the disease and the possibility of progressive joint damage. The concentration of soluble IL-2r, a product of T-cell activation, increases in serum and synovial fluid of active rheumatoid arthritis patients, too [Udagawa, N., Kotake, S., Kamatani, N., Takahashi, N., and Suda, T: The molecular mechanism of osteoclastogenesis in rheumatoid arthritis. Arthritis Research 4:281-289, 2002].
It is generally believed that Th1 type CD4+ T cells play an important role in the progress and continuation of rheumatoid arthritis. That is, CD4+ T lymphocytes stimulate macrophages and synovial cells to have inflammatory cytokines (TNF-α, IFN-γ, GM-CSF, IL-2, IL-6) and matrix metalloproteinase (MMP) secreted, for which signals were transmitted by soluble materials such as interferon-gamma (IFN-γ) and IL-17 and by cell surface component such as CD69. The secreted cytokines stimulate the proliferation of synovial membrane to form a pannus and destroy cartilage in cooperation with matrix metalloproteinase. The activated CD4+ T cells induce the activation of B cells through the contact with them on cell surface by CD40L, CD28, and a1b2 integrin, leading to the production of antibody containing rheumatoid factors. When CD4+ T cells are activated, osteoprotegerin ligand (OPGL) is expressed on the surface, which stimulates osteoclastogenesis, an important factor for bone destruction [Kong Y. Y., Feige U., Sarosi I., et al.: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteprotegerin ligand. Nature 402:304-309, 1999]. The activated macrophages and fibroblasts accelerate angiogenesis by secreting VEGF, FGF, etc. The activated vascular endothelial cells in synovial membrane make an amplified cycle of inflammation by secreting chemokine such as IL-8, inducing the expression of adhesion molecule and speeding up the infiltration of inflammatory cells. Rheumatoid arthritis is also believed to be a T-cell mediated autoimmune disease, which is related to the non antigen-specific intracellular interaction between T-lymphocytes and antigen-presenting cells. The reaction size of T-cells is determined by simultaneous stimuli induced by the interaction between a T-cell surface molecule and its' ligand. A major simultaneous stimulus signal is given by the interaction between T-cell surface receptors, CD28 and CTLA4, and their ligands such as B7-related molecules on antigen-presenting cells, that is CD80 (B7-1) and CD86 (B7-2) [Linsley, P. and Ledbetter, J.: The role of the CD28 receptor during T cell responses to antigen. Ann. Rev. Immunol. 11:191-212, 1993]. T-cell activation without simultaneous stimuli results in anergic T-cell response, indicating that immune system does not response to a stimulus [Schwartz, R. H.: Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell 71:1065-1068, 1992].
The treatment method for degenerative arthritis and rheumatoid arthritis in use is as follows. For the primary care, non-steroidal anti-inflammatory drug (NSAID) has been used, which improves patient's conditions but cannot prevent the progress of the disease and the damage of joint cartilage. In addition, such medicine is supposed to be administered for a long time, but long-term administration of the drug causes side effects in gastrointestinal system, central nervous system, hematopoietic tissues, kidney, liver, etc. So, half of the patients being treated with NSAID should give up the treatment within a year [Langenegger, T., Michel, B. A.: Drug treatment for rheumatoid arthritis., Clin Orthop. 366:22-30, 1999]. For the next treatment step, disease modifying anti-rheumatic drugs (DMARDs) such as gold drugs which are gold containing compounds like gold sodium thiomalate, gold sodium thiosulfate, etc, penicillamine and anti-malarials, have been used. Although these drugs reduce the progress of arthritis to some degree, they carry serious side-effects, too. Thus, only 5˜15% patients keep being treated with these drugs continuously after 5 years from the first administration of DMARDs. If no more therapeutic effects are expected from those drugs, the arthritic developed joint has to be replaced with artificial joint by surgical operation [Simon L. S., Int. J. Clin. Pract., 54:243-249, 2000].
Therefore, it is an urgent need to develop a new substance effective for the prevention and the treatment of arthritis related diseases, which has a new structure and functions to minimize side effects and toxicity, the limitations of the conventional therapeutic agents.
Thus, the present inventors have studied various physiological activities of Notoginseng radix, Rehmanniae radix preparata and Acanthopanacis cortex, and as a result the present inventors completed this invention by confirming that herbal mixture extract of Notoginseng radix, Rehmanniae radix preparata and Acanthopanacis cortex has no toxicity, inhibits the release of an inflammatory substance and the synthesis of a matrix destroying factor and suppresses the progress of arthritis, making it as a promising candidate without side effects for preventive and therapeutic agent as well as health food for arthritis related diseases.